Abstract: Plasma cells (PC) are responsible for maintaining serum antibody levels to pathogen. However, a comprehensive spatial map of PC subsets across tissue compartments in the human body is lacking. As a consequence, our understanding of global PC population structure across different tissues within individuals and also between different individuals is murky. Using unique and rare-to-access human tissue resources along with high-dimensional flow cytometry, will test the hypothesis that PC subset composition can be predicted by tissue site and that long-lived PC (LLPC) engage survival programs that are tailored to each site of origin. In Aim 1, we will identify known and novel PC subsets in lymphoid and mucosal tissues from normal human donors using complex flow cytometry and unbiased computational algorithms. We will integrate phenotype with signaling status and establish PC functional capabilities. In Aim 2, we will perform Next Generation RNA-Sequencing and functional assays on long-lived PCs (LLPC) derived from two distinct tissue sites in order to uncover shared versus tissue-specific survival pathways. Results from this study will reveal the global population structure of PC subsets responsible for human humoral immunity and provide insights into how PCs control infections regionally and systemically.